Cardiovascular disease, including, but not limited to, atheroslerosis, ischemia, reperfusion, hypertension, restenosis and arterial inflammation, is a major health risk throughout the world. Ischemia is a condition wherein there is a lack of oxygen supply in tissues or organs due to inadequate perfusion due to atheroslerosis or restenotic lesions, stroke, or anemia, to name a few. The most common cause of ischemia in the heart is atherosclerotic disease of the coronary arteries. Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, due to hypertension or aortic stenosis.
One of the most important therapeutic targets in the treatment of cardiovascular disease has been the protection of ischemic myocardium from necrosis. This has been a major focus for basic and applied research over the past 30 years. More recently, mechanisms of programmed cardiac cell death (apoptosis) have also been studied extensively. Both necrosis and apoptosis result in the irreversible loss of contractile performance. An unexplored corollary to protection from cell death is the enhancement of cell survival.
Heat shock proteins are involved in the folding, degradation and translocation of intracellular proteins (Benjamin I, et al., Stress (heat shock) proteins, (1998), Circ Res. 83: 117-132), but they also participate in the protection against apoptosis and in cell growth (Mehlen P. et al, Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks FAS/APO-1 and staurosporine-induced cell death. J Biol Chem. (1996); 271: 16510-16517; Beere H., et al, Heat-shock protein 70 inhibits apoptosis by preventing the recruitment of procaspase-9 to the Apaf-1 apoptosome, Nature Cell Bio., (2000); 2: 469-475; Li, C. et al., heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation, J Biol Chem., (2000); 275:25665-26571; Kamradt, M., et al., The small heat-shock protein αB-crystallin negatively regulates cytochrome c- and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation, J Biol Chem., (2001); 276: 16059-16063). They are crucial effectors of the program of cell survival, which protects cells against irreversible damage and accelerates functional recovery after stress (Latchman, D., Heat shock proteins and cardiac protection, Cardiovasc Res. (2001); 51: 637-646). Two main forms of heat-shock proteins in E. Coli, called DnaK and DnaJ, have been conserved in eukaryotes (Kelley, W., How J domains turn on Hsp70s., Cur Biol. (1999); 9: R305-R308). In mammalian cells, the chaperone HSP40 is the homologue of DnaJ. Several isoforms of DnaJ-like/HSP40 homologues have been cloned, that differ by their tissue distribution and their protein interactions. The role of these co-chaperones is to stimulate the ATPase activity of the cognate HSP70 (Russell, R., et al., DnaJ dramatically stimulates ATP hydrolysis by DnaK: insight into targeting of Hsp70 proteins to polypeptide substrate, Biochemistry, (1999); 38: 4165-4176; Minami, Y., et al., Regulation of the heat-shock protein 70 reaction cycle by the mammalian DnaJ homolog, Hsp4O, J Biol Chem., (1996); 271: 19617-19624) and to modulate its substrate-binding capacity. The heat-shock response is particularly developed in cardiac cells, which are long-lived, post-mitotic cells submitted to high oxidative stress (Williams, R., et al., Protective responses in the ischemic myocardium, J Clin Invest., (2000); 106: 813-818). During ischemia/reperfusion, this response is important to tilt the balance between cell survival and cell death.
Myocardial stunning refers to a form of non-lethal, fully reversible myocardial dysfunction that follows an acute episode of ischemia (Heyndrickx, G R, et al., Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs, J Clin Invest. (1975) 56: 978-985; Kloner, R A., et al., Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications: Part 1, Circulation, (2001); 104: 2981-2989). The syndrome of stunning is prevalent in different etiologies of coronary artery disease, including stable or unstable angina pectoris, myocardial infarction, and post-surgical dysfunction (Bolli, R., et al., Molecular and cellular mechanisms of myocardial stunning, Physiol Rev., (1999); 79: 609-634). Due to the major prevalence of ischemic heart disease, stunning is of paramount importance because it corresponds to a condition in which myocardial viability is maintained. Unraveling the molecular mechanisms of cardioprotection in stunned myocardium can open new avenues to salvage dysfunctional cardiac tissue and prevent cardiac cell loss. Especially, a better understanding of the mechanisms by which the molecular and cellular adaptations maintain cell survival should open new therapeutic opportunities.
It would, therefore, be beneficial to provide for specific genes, gene products, compositions and methods for the treatment and diagnosis of cardiac disease, including ischemic cardiac events, and to provide methods that would identify individuals with a predisposition for such conditions, and other types of cardiovascular disease or related conditions, and hence are appropriate subjects for preventive therapy.